Chronic Low Back Pain, Diabetic Neuropathic Pain
Conditions
Keywords
Asymmetric Diabetic Proximal Motor Neuropathy, Diabetic Autonomic Neuropathy, Diabetic Neuralgia, Diabetic Neuropathy, Painful, Neuralgia, Diabetic, Low back pain, chronic
Brief summary
The purpose of the study is to determine whether the combination of the the three drugs gabapentin, duloxetine, and donepezil are effective in treating pain in people with diabetic neuropathy or patients with failed low back syndrome (chronic back pain).
Detailed description
Neuropathic pain is a complex and likely heterogeneous disorder, and we recognize that clinically useful agents such as opioids, gabapentin, and antidepressants may be effective precisely because they have multiple mechanisms of action at multiple sites. This study, however, will not only provide important mechanistic information regarding one cascade which can be manipulated for analgesia, but will also provide much needed systematic and practical guidance for multi-drug therapy in patients with neuropathic pain. This study in patients with diabetic neuropathic pain and patients with failed low back syndrome, culminate in a quantitative description of interactions between activators of descending noradrenergic activity, norepinephrine transporter inhibitors, and cholinesterase inhibitors to exploit the plasticity of analgesia in chronic pain states. We will focus on practical applications, using clinically approved drugs, including gabapentin (Neurontin®) to activate noradrenergic activity, duloxetine (Cymbalta®) to inhibit the norepinephrine transporter, and donepezil (Aricept®), approved for the treatment of Alzheimer's dementia, but not previously tested to treat neuropathic pain, to inhibit cholinesterase. After the baseline measurements and physical examination patients will be trained to use a Personal Digital Assistant (PDA) to answer questions about their diabetic neuropathic pain or their chronic back pain. Upon successful completion of these tasks the patients will be randomized to receive one of the drug choices or placebo (inactive pill). The study will last for a total of 16 weeks and includes 5 visits to the research center with each visit lasting approximately 2 hours.
Interventions
DRUGdonepezil
Group 1: Will receive donepezil 5mg once a day
DRUGduloxetine
Group 2: Will receive duloxetine 30 mg twice a day
DRUGdonepezil 2.5 mg and duloxetine 30mg
Group 3: Will receive a combination of donepezil 2.5 mg and duloxetine 30mg
DRUGplacebo
Group 4: Will receive placebo pills
DRUGgabapentin
Week 8: all subjects will have open label gabapentin added to their randomized study medication
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Wake Forest University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of diabetic neuropathy * Age 18-80 * Willing to temporarily discontinue gabapentin or monoamine reuptake inhibitors upon entry into the study
Exclusion criteria
* Pregnancy * Allergy to study medications * Uncontrolled narrow-angle glaucoma * Currently being treatment with thioridazine (Mellaril) * Unstable medical conditions including cardiac, pulmonary, renal or hepatic diseases * Treatment with a monoamine oxidase inhibitor (MAOI) within 14 days of randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analog Scale for Pain | Study completion (16 weeks) | The primary outcome measure is the visual analog scale (VAS) for pain, a 10 cm line upon which the subject marks their intensity of pain. The line is anchored on the left as No pain at all and on the right as The worst pain imaginable. The score is the number of millimeters from the left origin of the line. The primary outcome measure for each period was the average value of all assessments for that period (2 weeks of measures for baseline, 6 weeks of measures for test drug alone, 6 weeks of measures for test drug plus gabapentin, and 2 weeks of measures for gabapentin alone). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Donepezil Donepezil 5 mg /day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15. | 5 |
| Duloxetine Duloxetine 30 mg twice per day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15. | 5 |
| Donepezil + Duloxetine Donepezil 2.5 mg /day and duloxetine 30 mg / day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15. | 6 |
| Placebo Placebo from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15. | 6 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Test Drug Alone | Failure of daily diary device | 1 | 1 | 2 | 2 |
| Test Drug Alone | Withdrawal by Subject | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Donepezil | Total | Placebo | Donepezil + Duloxetine | Duloxetine |
|---|---|---|---|---|---|
| Age, Continuous | 62 years | 60 years | 70 years | 59 years | 56 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 7 Participants | 1 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 15 Participants | 5 Participants | 4 Participants | 3 Participants |
| Region of Enrollment United States | 5 participants | 22 participants | 6 participants | 6 participants | 5 participants |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 3 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 14 Participants | 3 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 1 / 5 | 0 / 5 | 0 / 6 | 1 / 6 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 6 | 1 / 6 |
Outcome results
Primary
Visual Analog Scale for Pain
The primary outcome measure is the visual analog scale (VAS) for pain, a 10 cm line upon which the subject marks their intensity of pain. The line is anchored on the left as No pain at all and on the right as The worst pain imaginable. The score is the number of millimeters from the left origin of the line. The primary outcome measure for each period was the average value of all assessments for that period (2 weeks of measures for baseline, 6 weeks of measures for test drug alone, 6 weeks of measures for test drug plus gabapentin, and 2 weeks of measures for gabapentin alone).
Time frame: Study completion (16 weeks)
Population: As noted in patient flow, data are available for only 14 of 22 subjects due to failure of the electronic daily diaries used to assess pain during the study and to study discontinuation in some cases
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Donepezil | Visual Analog Scale for Pain | Gabapentin alone (2 weeks) | 2.2 units on a scale |
| Donepezil | Visual Analog Scale for Pain | Drug plus gabapentin (6 weeks) | 2.9 units on a scale |
| Donepezil | Visual Analog Scale for Pain | Test drug alone (6 weeks) | 4.1 units on a scale |
| Donepezil | Visual Analog Scale for Pain | Baseilne ( weeks) | 3.3 units on a scale |
| Duloxetine | Visual Analog Scale for Pain | Baseilne ( weeks) | 6.4 units on a scale |
| Duloxetine | Visual Analog Scale for Pain | Gabapentin alone (2 weeks) | 3.0 units on a scale |
| Duloxetine | Visual Analog Scale for Pain | Drug plus gabapentin (6 weeks) | 2.7 units on a scale |
| Duloxetine | Visual Analog Scale for Pain | Test drug alone (6 weeks) | 2.9 units on a scale |
| Donepezil + Duloxetine | Visual Analog Scale for Pain | Test drug alone (6 weeks) | 5.2 units on a scale |
| Donepezil + Duloxetine | Visual Analog Scale for Pain | Drug plus gabapentin (6 weeks) | 3.9 units on a scale |
| Donepezil + Duloxetine | Visual Analog Scale for Pain | Gabapentin alone (2 weeks) | 4.3 units on a scale |
| Donepezil + Duloxetine | Visual Analog Scale for Pain | Baseilne ( weeks) | 5.8 units on a scale |
| Placebo | Visual Analog Scale for Pain | Gabapentin alone (2 weeks) | 4.1 units on a scale |
| Placebo | Visual Analog Scale for Pain | Baseilne ( weeks) | 4.9 units on a scale |
| Placebo | Visual Analog Scale for Pain | Test drug alone (6 weeks) | 3.9 units on a scale |
| Placebo | Visual Analog Scale for Pain | Drug plus gabapentin (6 weeks) | 4.1 units on a scale |
Comparison: Due to failure of daily electronic diaries and exhaustion of funds, we were only able to recruit \< 30% of the number of subjects required in our power analysis.p-value: 0.69ANOVA